Anticonvulsant compounds

ABSTRACT

The present application relates to compounds and methods for reducing the severity of convulsant activity, or epileptic seizures.

FIELD OF THE INVENTION

The present invention relates to compounds with anti-convulsant and painactivity. These compounds are useful in modulating voltage-gated sodiumchannel activity and are thus useful in the treatment of epilepsy andchronic or acute pain.

BACKGROUND

Anti-convulsant compounds are presently in wide use in the treatment ofa variety of conditions and diseases, including epilepsy. Epilepsy is aneurological condition which affects the nervous system and causesindividuals with epilepsy to suffer from seizures. These seizures arecaused by disruptions in the electrical communication between neurons inthe brain. Epilepsy can be conceptualized as brain activity that isinappropriately synchronous. Seizures are often seen in electroencephalograms (EEGs) as high amplitude neural discharges that occuracross brain regions. This brain activity is accompanied by behavioraldisturbances that include loss of balance, jerking muscle movement,visual disturbances, and loss of consciousness. It is estimated thatabout 0.5% of the world's population has some form of epilepsy. Epilepsyis a lifelong condition, has a very low reversion rate, and is onlyrarely fatal. Persons with uncontrolled epilepsy are often under orun-employed.

The combination of all these factors makes epilepsy among the mostexpensive health care burdens in the world. In North America alone, thecost of epilepsy due to direct health care costs and lost economicactivity is estimated to be in the billions of dollars each year. Thereis no known cure for epilepsy.

The control of epileptic seizures is an unmet medical challenge. Currentmedications control seizures by targeting a number of sites in thecentral nervous system (CNS). These drugs, while effective, oftenproduce undesirable side effects that reduce compliance and thereforefficacy. Reportedly, nearly 30% of individuals with epilepsy do notrespond to any current therapies, including both drug and brainstimulation therapies. Accordingly, there is a need to develop novelanticonvulsants in order to provide effective alternatives for theseindividuals.

As well the management of acute and chronic pain is an ongoing problem.There are millions of people living with various forms of chronic pain.Blocking sodium channel function is one of many treatments.

SUMMARY OF THE INVENTION

In one embodiment, the present disclosure includes a method foreliminating or reducing the severity of convulsant activity or epilepticseizures by administering to a subject a therapeutically effectiveamount of an E and Z mixture of a compound represented by the formula(I).

-   Where R═H, CH₃, C₂ to C₆ (linear or branched), cC₃H₅, cC₅H₉, cC₆H₁₁,    CH═CH₂, or CH₂Ar-   R₁═R₂═H or CH₃-   R₃═R₄═H or CH₃-   R₅═H, CH₃, OCH₃, OCH₂Ar, Cl, or Br-   R₆═H or CH₃

In another embodiment, the method comprises administering to a subject atherapeutically effective amount of a compound represented by thefollowing chemical formula that is a mixture of E and Z isomers.

In yet another embodiment, the method comprises administering to asubject a therapeutically effective amount of the Z isomer of a compoundrepresented by the following chemical formula.

In another aspect, the present invention relates to a pharmaceuticalcomposition including a compound represented by the formula (I), or apharmaceutically acceptable salt or solvate thereof, together with apharmaceutically acceptable excipient.

In another embodiment, the composition includes a compound representedby the following chemical formula and is a mixture of E and Z isomers.

In yet another embodiment, the composition includes the Z isomer of acompound represented by the following chemical formula.

Further features of the invention will be described or will becomeapparent in the course of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

In order that the invention may be more clearly understood, preferredembodiments thereof will now be described in detail by way of example,with reference to the accompanying drawings, in which:

FIG. 1 is a side-by-side comparison of brain activity in a controlsample and in the presence of a preferred compound according to thepresent invention.

FIG. 2 is a graph showing the recovery time from inactivation ofvoltage-gated sodium channels in a control sample and in the presence ofa preferred compound according to the present invention.

DESCRIPTION OF PREFERRED EMBODIMENTS

It has been found that certain compounds, described herein, arevoltage-gated sodium channel inhibitors with anti-convulsive activity.Voltage-gated sodium channels are found in the neurons of the centraland peripheral nervous system and are responsible for generating therapid upstroke of the action potential. They are essential to thenervous system's ability to initiate and propagate electrical signals.

The present invention provides a compound represented by the followingformula (I):

-   Where R═H, CH₃, C₂ to C₆ (linear or branched), cC₃H₅, cC₅H₉, cC₆H₁₁,    CH═CH₂, or CH₂Ar-   R₁═R₂═H or CH₃-   R₃═R₄═H or CH₃-   R₅═H, CH₃, OCH₃, OCH₂Ar, Cl, or Br-   R₆═H or CH₃

The above compounds are obtained as a mixture of E and Z isomers.Compounds of the invention containing one or more asymmetric carbonatoms can exist as two or more stereoisomers. Included within the scopeof the invention are all stereoisomers of the compounds of the inventionand mixtures of one or more thereof.

The compounds represented by formula (I), are inhibitors ofvoltage-gated sodium channel activity and are useful in the treatment ofepileptic seizures and pain. Preferred compounds of the invention arethose listed in the Examples below and the pharmaceutically acceptablesalts and solvates thereof.

Epileptic seizures are caused by disturbances in the electrical activityof the brain. In particular, excessive electrical brain activity is ahallmark of an epileptic seizure. The electrical activity of the brainis primarily mediated by voltage-gated sodium channels. Thus, thedampening of voltage-gated sodium channel activity is a common target tocontrol epileptic disturbances.

The present invention also provides a method for eliminating or reducingthe severity of convulsant activity or epileptic seizures byadministering to a subject a therapeutically effective amount of acompound represented by formula (I), or a pharmaceutically acceptablesalt or solvate thereof, together with a pharmaceutically acceptableexcipient.

The compounds of the present invention may be administered orally,parenterally, or topically. Topical administration is preferred fortreatment of pain.

The compounds of the present invention may be prepared by the proceduresdescribed below. According to a first procedure, a preferred compoundrepresented by formula (I) may be prepared according to the followingmethodology, as illustrated by the reaction sequence shown below:

An alpha-lithiated nitrile (1) is prepared by reaction of thecorresponding nitrile with lithium diisopropylamide (LDA) in drytetrahydrofuran (THF) at −78° C. under a nitrogen atmosphere. Acyclohex-2-en-1-one, for example isophorone (2), is added to a THFsolution of the alpha lithio nitrile (1) at −78° C. The reaction mixturecan be quenched by addition a 10% NH₄Cl solution or allowed to warm to0° C. prior to quenching; this results in the formation of thehydroxynitrile (3).

In the next step the purified hydroxynitrile (3) is stirred with acatalytic amount of acid in toluene or dichloromethane at roomtemperature. This induces the loss of water from (3) and results,typically, in the formation of up to five isomers (4 a-4 c, 5E, and 5Z).

The mixture of isomers, when heated with ρ-toluenesulfonic (TsOH) acidin refluxing toluene, is converted cleanly to a mixture of the 5E and 5Zisomers.

The resulting mixture of stereoisomers may be separated, using knowntechniques for isolating individual enantiomers, including, for example,high pressure liquid chromatography. If enantiomers are present, ChiralHPLC may be used or the mixture may be reacted with a suitable opticallyactive compound, thereby converting the mixture into a diastereomericmixture, which may be separated using chromatography or fractionalcrystallization before converting one or both diastereoisomers back tothe corresponding pure enantiomer by known techniques.

General Procedure for the Preparation of diene nitriles.

General Procedure 1: Coupling Reaction

The desired nitrile is added drop wise via syringe to a −78° C. solutionof LDA (2M) in anhydrous THF (5-10 mL) under nitrogen atmosphere. Thissolution is stirred under these conditions for 5 min before adding theenone drop wise. The reaction mixture is kept at low temperature andquenched after 1 minute by addition of 10% aqueous NH₄Cl solution.Workup involves extraction with EtOAc (3×10 mL). The combined organicextracts are washed with water, dried over MgSO₄, filtered andconcentrated in vacuo. The product is purified by gradient columnchromatography using a gradient solvent system of EtOAc and hexanes.

General Procedure 2: Room Temperature Dehydration

The purified product obtained via general procedure 1 is stirred at roomtemperature in toluene (10-15 mL) containing a catalytic amount of PTSAuntil product formation is observed and the starting material has beenconsumed. The reaction mixture is quenched after 1 h with 10% aqueousNaHCO₃ and extracted with EtOAc (3×10 mL). The combined extracts arewashed with water, dried (MgSO₄), filtered, and concentrated in vacuo.Purification by column chromatography affords a mixture of up to fiveisomers.

General Procedure 3: Isomerization to the E/Z Isomers

The mixture from General Procedure 2 is dissolved in toluene containinga catalytic amount of PTSA and refluxed for three hours, then quenchedwith 10% aqueous NaHCO₃ and extracted with EtOAc (3×10 mL). The combinedextracts are washed with water, dried (MgSO₄), filtered, andconcentrated in vacuo. Purification by column chromatography affords theE/Z isomers of the desired compound.

Alternative sequence.

The crude hydroxyl compound obtained via General procedure 1 may besubjected directly to dehydration in refluxing toluene (GeneralProcedure 3).

EXAMPLE 1 Preparation of the E/Z Mixture of a Preferred Compound of thePresent Invention is Shown and Described Below

This compound is obtained following General Procedures 1, 2, and 3.General Procedure 1 is carried out starting with propionitrile (3.98 g,72.4 mmol), in anhydrous THF (10 mL), LDA (36.2 mL, 72.35 mmol), andisophorone (5 g, 36.8 mmol) in anhydrous THF (5 mL). The crude product(6.50 g) is purified by gradient column chromatography to yield a paleyellow oil as product (5.53 g, 78%, Rf=0.33 in 4:1 Hexanes:EtOAc).

The semi-purified coupling product is dehydrated, according to GeneralProcedure 2, to yield 5.20 g of a mixture of dienes, as a viscous oil(Rf=0.81 in 3:2 Hexanes:EtOAc) after column chromatography.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.43 (d, J=1.4 Hz), 6.17 (dd,        J=3.5, 1.8 Hz), 5.87-5.74 (m), 5.24-5.15 (m), 4.88 (d, J=19.2        Hz), 3.27 (dd, J=13.3, 6.8 Hz), 2.33 (d, J=1.4 Hz), 1.95 (ddd,        J=34.6, 16.8, 3.0 Hz,), 1.72 (d, J=1.6 Hz), 1.41 (dd, J=7.2, 0.7        Hz), 1.16-0.55 (m).

The above mixture of dienes is converted to a 5:4 mixture of E to Zdienes, according to General Procedure 3. Purification via columnchromatography affords 5.20 g of a pale yellow oil (Rf=0.81 in 3:2Hexanes:EtOAc). This material solidifies when stored in a freezer at−20C.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.45 (d, J=1.4 Hz), 6.18 (dd,        J=3.0, 1.5 Hz), 2.34 (d, J=1.4 Hz), 2.09 (d, J=0.7 Hz),        1.98-1.89 (m), 1.84 (d, J=5.1 Hz), 0.93 (s).

The 5:4 mixture of E to Z dienes is determined by comparison of theintegration of the peaks at 6.45 and 6.18 ppm due to the alkenehydrogens.

-   -   ¹³C NMR (100 MHz, CDCl₃) δ ppm 151.2, 149.9, 145.9, 144.0,        121.7, 121.0, 118.4, 99.3, 99.3, 45.2, 44.6, 43.2, 39.4, 31.2,        30.9, 28.2, 27.9, 24.6, 24.2, 15.5, 14.8.

The 5:4 E:Z diene mixture is recrystallized two consecutive times fromhexanes at room temperature to yield 91% pure E isomer.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.16 (dd, J=2.9, 1.4 Hz, 1H), 2.33        (d, J=1.3 Hz, 2H), 1.95 (s, 2H), 1.91 (s, 3H), 1.84 (s, 3H),        0.92 (s, 6H).    -   ¹³C NMR (100 MHz, CDCl₃) δ ppm 149.9, 145.9, 121.0, 118.5, 99.4,        45.3, 43.2, 31.3, 27.9, 24.6, 14.9.

EXAMPLE 2 Preparation of the E/Z Mixture of Another Preferred Compoundof the Present Invention(2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)pentanenitrile), is Shown andDescribed Below

The E/Z mixture is prepared according to the above scheme, following theGeneral Procedures 1, 2, and 3. For the isomerization (General Procedure3) 0.18 g of the five component mixture produced by General Procedure 2is refluxed for 3 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield 0.08 g ofa colorless oil.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.44 (dd, J=2.90, 1.43 Hz, 1H),        6.19-6.18 (m, 1H), 2.34 (s, 1H), 2.23 (td, J=18.47, 7.54, 7.54        Hz, 2H), 2.10 (s, 1H), 1.95 (d, J=7.78 Hz, 2H), 1.85-1.81 (m,        3H), 1.55 (dt, J=7.43, 7.37, 1.81 Hz, 2H), 0.93 (m, 9H)    -   ¹³C NMR (400 MHz, CDCl₃) δ ppm 150 7, 149.6, 145.8, 144.2,        121.9, 118.4, 105.6, 45.3, 44.8, 43.4, 39.4, 31.2, 31.0, 30.5,        28.2, 27.9, 24.6, 24.2, 21.9, 21.8, 13.4, 13.3

The 5:4 E:Z mixture is determined by comparison of the integration ofthe peaks at 6.44 and 6.19 ppm due to the alkene hydrogens.

EXAMPLE 3 Preparation of the E/Z Mixture of Another Preferred Compoundof the Present Invention(3-methyl-2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)butanenitrile) isShown and Described Below

The E/Z mixture was prepared according to the above scheme following theGeneral Procedures 1, 2, and 3. For the isomerization (General Procedure3) 0.05 g of the five component mixture produced by General Procedure 2is refluxed for 3 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield 0.04 g ofa colorless oil.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.43 (d, J=1.41 Hz, 1H), 6.24 (d,        J=1.27 Hz, 1H), 2.99-2.89 (m, 1H), 2.88-2.72 (m, 1H), 1.96 (d,        J=7.25 Hz, 2H), 1.84 (d, J=3.22 Hz, 2H), 1.12 (dd, J=6.79, 2.00        Hz, 6H), 2.34 (s, 3H), 2.14 (s, 3H), 0.93 (s, 6H)    -   ¹³C NMR (400 MHz, CDCl₃) δ ppm 148.9, 147.7, 145.8, 144.3,        122.2, 118.7, 118.4, 117.9, 113.1, 45.5, 44.9, 43.6, 39.4, 31.2,        31.0, 28.2, 27.9, 27.1, 26.6, 24.6, 24.2, 21.7, 21.6

The 2:1 E:Z which was determined by comparison of the integration of thepeaks at 6.43 and 6.24 ppm due to the alkene hydrogens.

EXAMPLE 4 Preparation of the E/Z Mixture of Another Preferred Compoundof the Present Invention(2-Cyclopropyl-2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)acetonitrile)is Described Below

The E/Z mixture is prepared according to the above scheme following theGeneral Procedures 1, 2, and 3. For the isomerization (General Procedure3) 0.1 g of the five component mixture produced by General Procedure 2is refluxed for 3 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield 0.09 g ofcolourless oil.

-   -   1H NMR (400 MHz, CDCl₃) δ ppm 6.44 (dd, J=2.97, 1.48 Hz, 1H),        6.40 (dd, J=2.94, 1.47 Hz, 1H), 2.27 (s, 3H), 2.33 (d, J=6.00        Hz, 2H), 1.96 (d, J=9.26 Hz, 2H), 1.84 (dd, J=13.25, 0.96 Hz,        3H), 0.93 (d, J=6.06 Hz, 6H), 0.86-0.80 (m, 2H), 0.69 (m, 2H)    -   ¹³C NMR (400 MHz, CDCl₃) δ ppm 151.7, 150.3, 145.9, 144.0,        137.8, 129.0, 128.2, 125.3, 122.1, 119.1, 118.5, 117.6, 108.1,        108.0, 45.5, 44.9, 43.6, 39.9, 31.3, 31.1, 28.3, 28.0, 24.7,        24.3, 21.4, 9.7, 9.1, 7.0, 6.9

The 1:1 E:Z is determined by comparison of the integration of the peaksat 6.44 and 6.40 ppm due to the alkene hydrogens.

EXAMPLE 5 Preparation of the E/Z Mixture of Another Preferred Compoundof the Present Invention(2-(3-methylcyclohex-2-en-1-ylidene)propionitrile) is Described Below

The E/Z mixture is prepared according to the above scheme following theGeneral Procedures 1, 2, and 3. For the isomerization (General Procedure3) 1.04 g of the five component mixture produced by General Procedure 2is refluxed for 3 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield 0.50 g ofcolourless oil.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.58-6.33 (m, 1H), 6.16 (dd,        J=2.90, 1.49 Hz, 1H), 3.74 (s, 1H), 3.42 (s, 1H), 1.72 (m)    -   ¹³C NMR (400 MHz, CDCl₃) δ ppm 190.3, 188.8, 42.5, 30.0, 29.7,        29.6, 29.6, 24.7, 24.4, 24.3, 23.0, 22.7, 21.7, 18.4

The 1:1 E:Z mixture is determined by comparison of the integration ofthe peaks at 6.65 and 6.16 ppm due to the alkene hydrogens.

EXAMPLE 6 Preparation of the E/Z mixture of Another Preferred Compoundof the Present Invention(2-(4,4-dimethylcyclohex-2-3nen-1-ylidenepropanenotrile) is DescribedBelow

The E/Z mixture is prepared according to the above scheme following theGeneral Procedures 1, 2, and 3. For the isomerization (General Procedure3) 0.04 g of the flushed material from the General Procedure 2 wasrefluxed for 3 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield 0.04 g ofcolourless oil.

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.48 (d, J=9.98 Hz, 1H), 6.23 (d,        J=10.07 Hz, 1H), 5.89 (t, J=10.05, 10.05 Hz, 1H), 2.68-2.61 (m,        2H), 2.43-2.38 (m, 2H), 1.91 (s, 3H), 1.60-1.52 (m, 2H), 1.04        (d, J=3.91 Hz, 1H)

The 1:1 E:Z mixture is determined by comparison of the integration ofthe peaks at 6.48 and 6.23 ppm due to the alkene hydrogens.

EXAMPLE 7 Preparation of the E/Z Mixture of Another Preferred Compoundof the Present Invention is Shown and Described Below

The E/Z mixture is prepared according to the above scheme following theGeneral Procedures 1 and 2. For the dehydration (General Procedure 2)0.62 g of the coupling product obtained from General Procedure 1 isstirred for 1 h in 10 mL of toluene containing a catalytic amount ofTsOH. The crude product is purified by chromatography to yield a paleyellow oil (0.53 g, 92%, Rf=0.74 in 7:3 Hexanes:EtOAc).

-   -   ¹H NMR (400 MHz, CDCl₃) δ ppm 6.37-6.32 (m, 0.5H), 5.96-5.85 (m,        0.4H), 4.88 (s, 0.4H), 4.77 (d, J=0.6 Hz, 0.5H), 2.26 (d, J=1.5        Hz, 1H), 2.04 (d, J=1.5 Hz, 1H), 1.90 (d, J=0.8 Hz, 2H), 1.77        (d, J=16.0 Hz, 3H), 0.85 (d, J=11.8 Hz, 6H).    -   HRMS: Calculated for C₁₁H₁₅N=161.24350, found=161.24054

The 5:4 E:Z mixture is determined by comparison of the integration ofthe peaks at 4.9 and 4.7 ppm due to the alkene hydrogens.

The compounds described in the above examples display activity in invitro and in vivo assays that track brain electrical activity. A firstassay is done using voltage sensitive dye imaging. This is done onisolated rat brain slices kept viable in artificial cerebral spinalfluid (ACSF). Electrically stimulating the slice activates the neuralassemblies therein. A voltage sensitive dye, such as, di-4-ANEPPS, isincubated with a brain slice for 1 hour in a suitable solution thatenhances the dye penetration into the tissue. The dye reacts to changesin voltage across the cell membrane of the neurons in the brain slice.The example compounds are added to the ACSF at known concentrationbetween 200 nM and 1 μM. The brain slices are then subjected to anelectrical stimulus that activates the neurons in the slice. As the dyereacts to the change in voltage, which can be observed and quantified,the degree to which activation of the brain is dampened by the presenceof the example compound is evaluated.

The compound of Example 1, exemplified above, was able to suppressactivation of the brain slice activity by 65±17% at a concentration of200 nM. In FIG. 1, the suppression of activity is shown by the reducedamplitude of the fluorescence change in layer II of the piriform cortexof a rat. As shown in FIG. 1, the compound of Example 1 suppressedactivation of rat brain slices prepared from the piriform cortex. In Atwo frames of a camera recording about 2 seconds after the stimulationare shown. The two frames shows the increased excitation of neurons inlayer 2 of the piriform cortex in response to a 60 Hz stimulus traindelivered through the lateral olfactory tract. In B two traces are shownthat quantify the increase in activity over a spot within layer 2, overthe course of the entire recording. The compound of Example 1 reducedboth amplitude and duration of the response. This is indicative of thecompounds ability to suppress brain activity.

In a second assay, the inhibition by the example compounds on theactivity of voltage-gated sodium channels is determined using patchclamp electrophysiology. This analysis is done on cultured corticalneurons isolated from rats.

The compound of Example 1 was tested at 100 nM and was shown to slow therecovery of sodium channel inactivation by about 3 fold (13 ms versus 35ms). As shown in FIG. 2, the upper curves represent the rate of recoveryin control recordings done on single neurons in culture. The dotted lineshows the single exponential fit of the rate of recovery. This was foundto have a time constant of 12.9 ms. The lower solid line represents thedata obtained in the presence of the compound of Example 1 (100 nM). Thelower dotted line is the single exponential fit of the rate of recovery.In the presence of the compound of Example 1 the rate of recovery wasfound to be slower having a time constant of 34.3 ms.

The example compounds prolong the time required for voltage-gated sodiumchannels to recover from a normally occurring inactive state induced bydepolarization. At high levels (frequency) of sodium channel activitythese compounds are more effective in dampening activity than at low(non-seizure) levels of activity. Thus, the example compounds tend tosuppress abnormal brain behavior to a higher degree than normal brainbehavior.

A number of embodiments of the present invention have been described.Nevertheless, the embodiments are described herein illustratively andare not meant to limit the scope of the invention, as claimed.Variations of the foregoing embodiments will be evident to a person ofordinary skill and are intended by the inventor to be encompassed by thefollowing claims.

What is claimed is:
 1. A method for reducing the severity of convulsantactivity, comprising administering to a subject a therapeuticallyeffective amount of a compound represented by the following formula (I):

wherein, R═H, CH₃, C₂ to C₆ (linear or branched), cC₃H₅, cC₅H₉, cC₆H₁₁,CH═CH₂, or CH₂Ar, R₁═R₂═H or CH₃, R₃═R₄═H or CH₃, R₅═H, CH₃, OCH₃,OCH₂Ar, Cl, or Br, and R₆═H or CH₃.
 2. The method of claim 1, whereinR═H, CH₃, C₂ to C₆ (linear or branched), cC₃H₅, cC₅H₉, or cC₆H₁₁.
 3. Themethod of claim 2, wherein R₅═H or CH₃.
 4. The method of claim 3,wherein R═H, CH₃, or C₂ to C₆ (linear or branched).
 5. The method ofclaim 4, wherein R═H or CH₃.
 6. The method of claim 1, wherein thecompound represented by the formula (I) is a compound represented by thefollowing formula:


7. The method of claim 1, wherein the compound represented by theformula (I) is 2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)pentanenitrile.8. The method of claim 1, wherein the compound represented by theformula (I) is3-methyl-2-(3,5,5-trimethylcyclohex-2-en-1-ylidene)butanenitrile.
 9. Themethod of claim 1, wherein the compound represented by the formula (I)is a compound represented by the following formula:


10. The method of claim 1, wherein the compound represented by theformula (I) is a compound represented by the following formula:


11. The method of claim 1, wherein the compound represented by theformula (I) is a compound represented by the following formula:


12. The method of claim 1, wherein the compound represented by theformula (I) is a compound represented by the following formula: